17alpha-ethynyl-13beta-n-propyl-delta5(10)-gonene-17beta-ol-3-one, its esters and use



United States Patent Olice 3,407,255 Patented Oct. 22, 1968 3,407,25517a-ETHYNYL-13fi-n-PR0PYL-A -GONENE-flp. ol-3-0NE, ITS ESTERS AND USERobert Joly, Montmorency, Val-d-ise, and Jnlien Warnant,Neuilly-sur-Seine, France, assignors to Roussel-UCLAF, S.A., Paris,France, a corpora- 'tion of France No Drawing. Continuation-impart ofapplication Ser. No. 273,295, Apr. 16, 1963. This'application July 27,1964, Ser. No. 385,503 I a 2 Claims. (Cl. 424-243) ABSTRACT OF THEDISCLOSURE The present invention relates to the use of 17a-ethynyl-13B-n-propyl-A -gonene-17;8ol-3-one and esters thereof with organiccarboxylic acids having from 1 to 18 carbon atoms corresponding to thefollowing Formula I;

tie-CH 2 wherein R represents a member selected from the groupconsisting :of hydrogen and the acyl radical of an organic carboxylicacid having from 1 to 18 carbon atoms, as a medicine for itsprogestornimetic action.

pled with a weak hypophysial inhibitory action against theover-secretion of folliculo-stimulating gonadotropic hormones (F.S.H.factory) and practically non-existent estrogenic activity.

The invention has for its object the development f gonene compounds ofthe formula CECH wherein R represents a member selected from the groupconsisting of hydrogen and the acyl radical of an organic carboxylicacid having from'l to 18 carbon atoms, and particularly 17ozethynyl-13,9-n-propyl-A -gonene 17,8- ol-3-one.

A further object of the invention is the process of ob- 5 taining aprogestomimetic response in warm-blooded animals which comprisesadministering from about 1 mg./ kg. to about 15 mg./kg. per day of thegonene compound of the formula wherein R represents a member selectedfrom the group consisting of hydrogen and the acyl radical of an organiccarboxylic acid having from 1 to 18 carbon atoms, and particularly 17aethynyl-13,8-n-propyl-A -gonene-175- ol-3-one.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

It has now been found that gonene compounds of the formula Gil -CH--(EECH acetone, benzene and chloroform and insoluble in water.

, Its melting point determined on the Kofler block is 172 C. and itsspecific rotation [u] =+91 (c.=0.4% in methanol).

Infrared spectra shows the presence of a hydroxyl band, the presence ofan ethynyl group, and the presence of a band at 1715 cm.- correspondingto a non-conjugated ketone.

17a ethynyl-13B-n-propyl-A -gonene-l7fl-ol-3-one is prepared as shown inUnited States Patent No. 3,136,790. The principle of preparationconsists in that 17a-ethynyl- 13fi-n-propyl-A -gonadiene-17B-ol-3-one issubjected to the action of a metal selected from the group consisting ofalkali metals and calcium in the presence of liquid ammonia and a protondonor. The most advantageous metal is lithium. In the process,unexpectedly, the acetylenic bond is not affected.

The reaction occurs at temperatures between about -30 C. and 80 C.,preferably between about -60 C. and C. As proton donors, it ispreferable to utilize lower alkanols such as methanol and ethanol whichalso have a solvent effect. The reaction can be conducted in thepresence or absence of another solvent inert to 3 the action of themetals employed, preferably the lower alkyl ethers such as ethyl orisopropyl ether or the cyclo-' alkyl ethers such as dioxane andtetrahydrofuran.

The reaction scheme follows the following flow diagram:

M represents an alkali metal or calcium.

17a-ethynyl-l3fi-n-propyl A gonadiene-17B-ol-3- one, the startingcompound, was prepared according to the method described in copending,commonly assigned The product thus obtained is identical to the productobtained according to the first process described above. 3-methoxy-l7a-ethynyl-ISfl-n-propyl Azlwo) gonadiene- 176-01 is obtainedstarting from IBfi-n-propyl-nor-estra- 5 diol described by Velluz etal., Tetrahedron Letters No.

cit -cs v 3, pp. 127-130 (1961). The following flow diagram shows thepassageof 13fl-n-propyl-nor-estradiol to 3-methoxy- 17a-ethynyl 136n-propyl A gonadiene-17fi-ol,

United States patent application Ser. No. 204,057, filed 20 then to thefinal 17a-ethynyl-13fl-n-propyl-M gonene June 21, 1962.

Hem-propylnor-estradiol TABLE I l Aluminium isopropylatse l7a-ethynyl-133-n-propyl A501?) gonene-17Bol-3-one (I, R=I-I) can also be prepared byacid hydrolysis of 3-methoxy-17a-ethynyl-13fi-n-propy1 A gonadiene-l73-ol. This hydrolysis is effected preferably with aqueous acetic acid atordinary temperatures. By the addition of water,17a-ethyl-13fl-n-propyl-N -gonene-lIp- 0l-3-one precipitates. Thecompound is purified by recrys' tallization from isopropyl ether byheating and cooling.

When desired, 17a-ethynyl-l3fl-n-propyl-A -gonene- 17B-ol-3-one can beesterified by the action of a functional 70 derivative, such as the acidchloride or acid anhydride, of

an organic carboxylic acid having from 1 to 18 carbon atoms.

The organic carboxylic acids having from 1 to 18 carbon atoms are thoseof aliphatic or cycloaliphatic, satu- 5 rated or unsaturated carboxylicacids or those of aromatic or heterocyclic carboxylic acids: Forexample, alkanoic acids, such as formic acid, acetic acid, propionicacid,

butyric acid, isobutyric acid, valeric acid, isovaleric acid,trimethylacetic acid, caproic acid, p-trimethylpropionic acid, oenanthicacid, caprylic acid, pelargonic acid, capric acid, undecylic acid,lauric acid, myristic acid, palmitic acid, stearic acid; alkenoic acids,such as undecylenic acid, oleic acid; cycloalkanoic acids, such ascyclopentylcarboxylic acid, cyclopropyl-carboxylic acid,cylobutylcarboxylic acid, cyclohexyl-carboxylic acid; cycloalkylalkanoicacids, such as oyclopropylmethyl-carboxylic acid, cyclobutylmethylcarboxylic acid, cyclopentylethyl carboxlic acids,cyclohexylethyl-c-arboxylic acid; arylalkanoic acids, such asphenylacetic acid, phenylpropionic acid; benzoic acid; phenoxyalkanoicacids, such as phenoxyacetic acid,p-chlorophenoxyacetic acid,2,4-dichlorophenoxyacetic acid, 4-t.-butylphenoxyacetic acid,3-phenoxypropionic acid, 4-phenoxybutyric acid; heterocyclic-carboxylicacids, such as furane-Lcarboxylic acid, 5-t.-butylfurane-Z-carboxylicacid, S-bromofurane 2 carboxylic acid, nicotinic acid; B-ketocarboxylicacids, such as acetylacetic acid, propionylacetic acid, butyrylaceticacid; aminoacids, such as diethylaminoacetic acid, aspartic acid, etc.

The following examples are illustrative of the invention. They are not,however, to be construed as lirnitative. It is obvious that otherexpedients known to the art may be employed.

EXAMPLE I Preparation of 17oc-ethynyl-13fi-n-propyl- -gonene-17B-ol-3-one (I, R=H) by reduction of the corresponding A -steroid -gm. ofl7u-ethynyl-13B-n-propyl-A -gonadiene-17,6- ol-3-one were dissolved in amixture of 50 cc. of methanol and 140 cc. of anhydrous tetrahydrofuranunder an atmosphere of nitrogen. The solution obtained was cooled to 70C. 140 cc. of liquid ammonia were added. Then, over a space of tenminutes; about '535 mgjof finely pulverized lithium were introduced. Themixture was subjected to agitation under cooling towards 70 C. for aperiod'of about ten minutes. Next, the reaction mixture was poured intoa mixture of water and ice. The mixture was agitated for a period ofabout two hours. The precipitate formed was vacuum filtered, washed withwater until the wash waters were neutral, and dried. 9.657 gm. of raw17a-ethynyl-13fl-n propyl-A -gonene-l7 8-ol-3-one were obtained. Theproduct was purified by recrystallization from isopropyl ether. Thepurified product had a melting point 172 C. and a specific rotation [u]=+91 (c.=0.4% in methanol).

The product was soluble in alcohol, ether, acetone, benzene andchloroform and insoluble in water.

This compound was not described in the literature prior to ourinvention.

17a-ethyny1-13B-n-propyl-A -gonadiene 17,8-01-3-one, the startingcompound, was prepared according to the method described in UnitedStates patent application Ser. No. 204,057, filed June 21, 1962.

EXAMPLE II Preparation of 17a-ethynyl-13/8-n-propyl-A-gonenel7fl-ol-3-one Step A: Preparation of 3-methoxy-13pJ-n-propyl-A-gonatriene-l7fi-ol.-A suspension of 17 gm. of 13/3-n-propyl-l8-nor-estradiol in 85 cc. of acetone, dissolved by addition of43 cc. of 1.95 N sodium hydroxide solution, was agitated at 20 C. for aperiod of 5 minutes under nitrogen. The reaction mixture was heated toreflux and 7 cc. of dimethyl sulfate were introduced into the solution.The solution was allowed to remain at reflux for a period of an hour anda half and during this time, in two lots, 28 cc. of sodium hydroxidesolution, then 4 cc. of dimethyl sulfate were introduced.

The solution was cooled to 15 C. Water was added thereto. The solutionwas filtered. The precipitate was vacuum filtered and washed untilneutral.

17.850 gm. of 3-methoxy-13/3-n-propyl-A -gonatriene-17 8-ol wererecovered having a melting point of 103-104 C. and a specific rotation[oz'] =+62.3 (c.=0.25% in ethanol).

This compound was not described in the literature prior to ourinvention.

Step B: Preparation of 3-methoxy-13B-n-pr0pyl-A gonadiene-17B-ol.17.2gm. of the product obtained in Step A were dissolved in 140 cc. oftetrahydrofuran. The solution was cooled to 35 C. and 172 cc. of liquidammonia were introduced. Then slowly 2.7 gm. of lithium were added. Thesolution was maintained under agitation for a period of 18 minutes andthe ammonia was allowed to evaporate.

The mixture was precipitated with water. The precipitate was separated,washed with water, vacuum filtered and dried. 22.5 gm. of3-methoxy-13,3-n-propyl-A gonadiene-17,B-ol were recovered having amelting point of -125 C.

This compound was not described in the literature prior to ourinvention.

Step C: Preparation of 3-methoxy-13,3-n-propyl-A gonadiene-17-one.-22.5gm. of the compound obtained according to Step B were dissolved in 255cc. of toluene under nitrogen and while agitating. The solution wasconcentrated and heated to 100 C. 374 cc. of methylethyl ketone and 260cc. of toluene containing 6.8 gm. of aluminum isopropylate wereintroduced into the solution in the space of 4 hours. The refluxing wascontinued for a period of 15 minutes While distilling. Then the mixturewas cooled to 20 C. 10 cc. of water were introduced into the reactionmixture under agitation. The precipitate of alumina was filtered andwashed twice with 20 cc. of toluene each time. The toluene wash liquorswere added to the reaction mixture. Then the toluene was removed fromthe reaction mixture by entrainment with water vapor. Water wasintroduced into the suspension obtained. The precipitate was vacuumfiltered, washed and dried under vacuum.

17.5 gm. of 3-methoxy-13fl-n-propyl-A -gonadiene- 17-one were recoveredhaving a melting point of 117- 118 C.

An analytical sample showed a melting point of 122 C. and a specificrotation of [u] =|16l (c.=0.25% in ethanol).

Step D: Preparation of 3-methoxy-13fi-n-propyl-17aethynyl-A-gonadiene-l7,8ol.5.9 gm. of a product obtained according to Step C wereintroduced at 30 C. into a solution of ethynyl magnesium bromide intetrahydrofuran. The reaction mixture was heated to reflux whilebubbling acetylene therethrough for a period of 2 hours. Next, thereaction mixture was cooled to +5 C. A suspension was obtained which waspoured into ice water containing 360 gm. of ammonium chloride. Theprecipitate was separated, vacuum filtered, washed and dried undervacuum. 6.470 gm. of 3-methoxy-l3B-n-propy1-17aethynyl-A-gonadiene-176-01 were recovered having a melting point of 125127 C.After recrystallization, an analytical sample showed a melting point ofC.

This compound was not described in the literature prior to ourinvention.

Step B: Preparation of 17a-ethynyl-13/3-n-propyl-Agonadiene-17fi-ol-3-one.1.6 gm. of the product obtained according toStep D were dissolved in 24 cc. of a 75% acetic acid solution. Aftertotal dissolution, the product crystallized. The suspension wasmaintained at 20 C. under agitation for a period of 15 minutes. Then itwas poured into 120 cc. of water. The precipitate was separated, vacuumfiltered, washed and dried under vacuum.

1.530 gm. of raw 17u-ethynyl-13/3-n-propyl-A .gonene-l7fi-ol-3-one wereobtained which product was purified by recrystallization. The purifiedproduct had an 7 instantaneous melting point of 172 C. and a specificrotation of [a] =+91 (c.=0.4% in methanol).

The product occurred in the form of a colorless, solid compound,crystallized in quadrangular prisms, and was soluble in alcohol, ether,acetone, benzene and chloroform and insoluble in water.

Infrared spectra showed the presence of a hydroxyl band, the presence ofan ethynyl group, and the presence of a band at 1715 cm.- correspondingto a non-conjugated ketone.

This compound was not described in the literature prior to ourinvention.

As previously stated, esters and the free alcohol of 17aethynyl 135n-propyl-A -g0nene-l7fi-ol-3-one I, are possessed of interestingpharmacological properties. They possess particularly an importantprogestomimetic action while being practically devoid of estrogenicactivity.

The product can be utilized in therapy in warm} blooded animals where aprogestomimetic action, free from adverse side elfects, is desirable.

17a ethynyl 13,3-n-propyl-A -gonene-l7fl-ol-3-one and its esters areutilized orally, 'perlingually, transcutaneously and rectally.

They can be prepared in the form of injectable solutions or suspensions,prepared in ampules or in multipledose fiacons, in the form of implants,tablets and suppositories.

The useful dosology is controlled between 1 mg./kg. and mg./kg. per doseand per day in the warmblooded animal as a function of the method ofadministration. The pharmaceutical forms such as injectable solutes andsuspensions, tablets, glossettes or suppositories are prepared accordingto the usual processes.

EXAMPLE III Pharmacological study of 17a-ethyny1-13,8-n-propyl- A-gonene-17B-ol-3-one (a) Determination of the progestomimeticaction.-The progestomimetic action of Hot-ethynyl-13,3-n-propyl- A-gonene-1718-01-3-0ne was determined by the Clauberg test elfected onrabbits previously sensitized by the administration of folliculine. Themedicine was administered orally at doses of 4 mg. per day for a periodof 5 days. The animals were sacrificed on the 6th day and autopsied.They presented at the autopsy the characteristic lacy proliferation ofthe endometrium. All the rabbits thus treated presented such astructure, very well developed.

Comparable activity according to the above test was determined between170: ethynyl 1313 n-propyl-A gonene-l7fl-ol-3-one and bothl7a-ethynyl-l9-nor-testosterone and its A isomer, l7a-ethynyl-A-estrene- 17fl-ol-3-one. Under oral administration of the threecompounds the following ratio of activities was observed:

Table II.-Progestomimetic actionClauberg test Oral administrationActivity ratio 17a-ethynyl-13/3-n-propyl-A -gonene 17fi-ol 3-one 217a-ethynyl-19-nor-testosterone 1 17u-ethynyl A -estrene-17,8-ol-3-oneAbout 0 Table III.-Estrogenic activityAllen-Doisy test-- Oraladministration Activity ratio 17 a-ethynyl-estradiol l 17a-ethynyl-A-estrene-l7/3-ol-3-one 1/ 30 17a ethynyl 13fi-n-propyl-A -gonene-178-01-3- one 1/30 On subcutaneous injection of the three compounds, thefollowing ratio 'of'estrogenic activities was observed: TableIV.Estrogenic activity-Allen-Doisy test v subcutaneously Activity ratiol7u-ethynyl-estradiol 1 17a-ethynyl-A -estrene-17B-ol-3-one 1/ 300 17aethynyl-l313-n-propyl-A -gonene-175-ol-3- I one l/30 171xethynyl 13B npropyl-A -gonene- 17fi-ol-3-one has a marked diminution of estrogeniceffect as determined by the Allen-Doisy test comparable to that of17aethnyl-A -estrene-17,B-o1-3-one, as compared with ethynyl-stradiol. 7

Test of the weight of the uterus Comparative activity according to theweight of the test of the uterus for estrogenic activity on both oraladministration and subcutaneous injection was determined between 17aethynyl-13/9-n-propyl-A -gonene-17 8-01-3- one and both17u-ethynyl-estradiol and 17u-ethyi1yl A -estrene-17(3-01-3-one.

On ,oral administration of the three compounds, the followingvratio ofestrogenic activities was observed:

Table V.Estrogenic activityTest of weight of the uterus0rally Activityratio 17a-,ethynyl-estradiol 1 17a-ethynyl-A m-estrene-17B-ol-3-one 1/40 17a ethynyl-13fi-n-propyl-A i f -gonene 17,6-01- 3-one 1/1800 Onsubcutaneous injection of the three compounds, the following ratio ofestrogenic activities was observed:

Table VI.-Estrogenic activity-Test of weight of theuterus-Subcutaneously v Activity ratio 17a-ethynyl-estradiol 117a-ethynyl-A -estrene-l7,8-ol-3-0ne l 200 l7a-ethynyl- 13 fl-n-propyl-A-gonene l7fl-ol- 3-one 1/3500 17oeethynyl-13 8-n-propyl-A D-gonene-17Bol 3-one comparable activity.

(0) Study of the retarding action on hypophysis-The retardingaction onhypophysisof 17a-ethynyl-13 8-n-propyl-A l-gonene-176:01-3-one (I, R=H)was evaluated on castrated female rats united parabiotically with entirerats. I

The parabios test enables a quantitative appraisal of the increase ofhypophysial gonadotropic activity of the eastrated subject by measuringthe weight of ovaries of the intact partner. This hypertrophy of gonadesafter castration can be inhibited by androgenic or estrogenic sexualhormones, but with all the inconveniences that comprise their hormonalactivity. The present compounds are practically devoid of the lattertype of activity.

The technique of the parabios test is the following: 30- day old femalerats of the same litter are united in parabiotic union according to themethod described by Bunster et a1. (Anat. Rec., 1933, 57, 339). One ofthe pair was castrated and treated the same day with 17a-ethynyl-13/3-n-propyl-A -gonene-17/8-ol-3-one. The animals received the medicinefor a period of days.

The animals were sacrificed the eleventh day after the parabiotic union.The genital organs were separated and weighed. It is known in eifectthat castration causes a hypersecretion of hypophysial gonadotropichormones which causes in animals united in panabiotic union, an increasein weight of the ovaries and the uterus of the entire rat byfolliculinic stimulation.

In this test, 17a-ethynyl-13B-n-propyl-A -gonene- 17fl-ol-3-one wasadministered for a period of 10 days orally at up to a dose of 200 insuch a fashion as to find out the threshold dose provoking totalhypophysial inhibition.

The results obtained are resumed in Table VII below. These comparativetests were effected simultaneously by the administration under the sameconditions of 17aethynyl-A -estrene-17fi-ol-3-one at doses of 150 and200 per day.

CH2 on wherein R is a member selected from the group consisting ofhydrogen and the acyl radical of an organic carboxylic acid having from1 to 18 carbon atoms.

2. The process of obtaining a progestomimetic response TABLE VII AverageAverage Average Dose weight of the weight of the weight of theHypophysial Treatment administered, uterus of the uterus of the ovariesof the inhibition in castrated rats entire rats in entire rats inpercent in mg. mg. mg. Control 0 32 137 168 17a-cth ynyl-N-estrene-17fl-ol-3-one 200 133 132 27. 7 92. 9 150 136 131 19 10017a-ethynyl-13B-n-propyl-A -g0nene-17fl-ol-3- one 200 60 Inlnbitlonplateauing at 50% to 75% 01 the cases 17a-ethynyl-13/8-n-propyl-A-gonene-17 9 ol 3-one causes between 50% to 75% inhibition againstoversecretion of the F.S.H. factor. Increasing dosage levels do noteffect a further increase in this level of inhibition.

((1) Androgenic and anabolic action.Comparable to 17u-ethynyl-A-estrene-17fl-ol-3-one, the compound of the invention, l7u-ethynyl-l38-n-propyl A -gonene- 17fl-ol-3-one was practically completely devoid ofandrogenic and anabolic action at comparable standard doses.

17a-ethynyl-13,8-n-propyl-A -gonene-17B o1 3-one is thus effective as anoral progestomimetic agent while having only a weak hypophysialinhibitory action and a practically non-existent estrogenic, androgenicand anabolic action. It is thus eflective as an oral progestomimeticwithout adverse side effects.

It is to be understood that the invention is not to be References CitedUNITED STATES PATENTS 2,725,389 11/1955 Colton 260397.4 2,830,063 4/1958 Clinton et 'al. 260397.5 3,062,713 11/1962 Ruggieri et al. 167--533,075,970 1/1963 Nomine et al 260239.55

OTHER REFERENCES Fried et al.: J.A.C.S., 83, p. 4663-64 (1961).

H. A. FRENCH, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 407255 Dated October 2 2 1968 Inventor(s) Robert y 12 8.1

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 8 French Priority Applications PV 895,563 dated April 25,l!

and PV 905,184 dated July 26, 19

were not indicated in the patent Signed and sealed this 30th day of May1972.

(SEAL) Attest:

ROBERT GOTTSCHALK EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer

